Correspondence
Kidney-Transplant Rejection and Anti-MICA Antibodies
N Engl J Med 2008; 358:195-196January 10, 2008
- Article
To the Editor:
With respect to the report by Zou et al. (Sept. 27 issue)1 on kidney-transplant rejection and major-histocompatibility-complex (MHC) class I–related chain A (MICA) antibodies, caution is needed in asserting that presensitization against MICA antigens might contribute to allograft loss among recipients who are well matched for HLA. Not stated are possible variations in the methodologies, testing criteria, and cutoff values used for anti-HLA–antibody testing and panel-reactive antibody determination among the 20 centers in 13 countries that participated in the study from 1990 to 2004. Moreover, whereas the detection of anti-MICA antibodies was retrospectively performed by one laboratory using a very sensitive and specific technique (single antigens with the use of a Luminex platform), the detection of anti-HLA antibodies was performed with the use of a less sensitive technique (enzyme-linked immunosorbent assay [ELISA] kits) that may not reliably detect all HLA class I and class II antigens, including Cw, DQ, and DP specificities.2-4 Anti-HLA–antibody testing criteria for ruling out reactivity to these HLA antigens should be clearly specified in patients who have positive tests for anti-MICA antibodies. Thus, the apparent association of anti-MICA antibodies with graft loss in recipients with good HLA-A, HLA-B, and HLA-DR matches could be influenced by the simultaneous presence of undetected anti-HLA antibodies.
4 ReferencesMalek Kamoun, M.D., Ph.D.
Robert A. Grossman, M.D.
University of Pennsylvania School of Medicine, Philadelphia, PA 19104
malekkam@mail.med. upenn. edu 1
Zou Y ,Stastny P ,Susal C ,Dohler B ,Opelz G . Antibodies against MICA antigens and kidney-transplant rejection. N Engl J Med 2007;357:1293-1300
Full Text | Web of Science | Medline2
Terasaki PI ,Ozawa M ,Castro R . Four-year follow-up of a prospective trial of HLA and MICA antibodies on kidney graft survival. Am J Transplant 2007;7:408-415
CrossRef | Web of Science | Medline3
El-Awar N ,Lee J ,Terasaki PI . HLA antibody identification with single antigen beads compared to conventional methods. Hum Immunol 2005;66:989-997
CrossRef | Web of Science | Medline4
Qiu J ,Cai J ,Terasaki PI ,El-Awar N ,Lee JH . Detection of antibodies to HLA-DP in renal transplant recipients using single antigen beads. Transplantation 2005;80:1511-1513
CrossRef | Web of Science | Medline
To the Editor:
Zou et al. report an association between pretransplantation antibodies against MICA antigens and allograft loss in patients with acute kidney-transplant rejection. Anti-HLA antibodies are closely associated with acute humoral rejection in kidney allografts.1 It would be important to know whether anti-MICA antibodies induce humoral or cellular rejection. However, information on the definition used to diagnose acute rejection (biopsy-proven or not) and its histologic type and severity is not provided in the article. Such data would provide an insight into the mechanism of allograft loss and might help in the development of strategies for prevention and treatment of rejection associated with these antibodies. Furthermore, the authors did not find any association between the number of blood transfusions before transplantation and the presence of anti-MICA antibodies. Pregnancy has also been reported to be associated with immunization against MICA.2 It would have been interesting to examine pregnancy as a possible source of immunization in these patients.
2 ReferencesSeema Baid-Agrawal, M.D., F.A.S.N.
Ulrich A. Frei, M.D.
Charité Universitätsmedizin, 13353 Berlin, Germany
seema.baid-agrawal@charite. de 1
Moll S ,Pascual M . Humoral rejection of organ allografts. Am J Transplant 2005;5:2611-2618
CrossRef | Web of Science | Medline2
Mizutani K ,Terasaki PI ,Shih RN ,Pei R ,Ozawa M ,Lee J . Frequency of MIC antibody in rejected renal transplant patients without HLA antibody. Hum Immunol 2006;67:223-229
CrossRef | Web of Science | Medline
To the Editor:
The magnitude of the effect of MICA antibodies on early graft survival, as reported by Zou et al., seems surprising, especially considering the low rejection rates with modern immunosuppression; indeed, acute rejection as a cause of early graft loss has almost disappeared.1 The authors state that their study demonstrates an increased rate of acute rejection among patients who are positive for MICA antibodies, and they refer to Figure 1 of their article, which shows graft survival. The ongoing mention of graft loss secondary to acute rejection in the article appears to be highly speculative and may be misleading, since no data on acute rejection or other causes of graft loss are presented. Since this is key in justifying the relationship between MICA antibodies and the higher graft-loss rates, this hypothesis seems questionable. Because this is a retrospective study, other covariates (collected or not collected) disproportionally represented in the cohorts might explain the difference observed, and a multivariate analysis might actually attenuate or negate the association. In a recent study, MICA antibodies did not correlate with rejection or C4d deposition.2
2 ReferencesDuska Dragun, M.D.
Charité Universitätsmedizin, 13353 Berlin, Germany
duska.dragun@charite. de Juan Scornik, M.D.
Herwig-Ulf Meier-Kriesche, M.D.
University of Florida College of Medicine, Gainesville, FL 321601
Meier-Kriesche H-U ,Schold JD ,Srinivas TR ,Kaplan B . Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004;4:378-383
CrossRef | Web of Science | Medline2
Scornik JC ,Guerra G ,Schold JD ,Srinivas TR ,Dragun D ,Meier-Kriesche HU . Value of posttransplant antibody tests in the evaluation of patients with renal graft dysfunction. Am J Transplant 2007;7:1808-1814
CrossRef | Web of Science | Medline
Author/Editor Response
We thank Kamoun and Grossman for their comments. Tests performed by ELISA tend to be less sensitive than those using Luminex. Therefore, some patients considered to have no panel-reactive HLA antibodies might have had antibodies against HLA below the threshold of detection. Whereas the presence of antibodies against MICA antigens was highly correlated with a poor outcome, it was less associated with poor outcome in patients with HLA antibodies detected by ELISA. It therefore seems unlikely that undetected weak antibodies against HLA could have been the reason for the association of anti-MICA antibodies with graft loss. Furthermore, the association was highly correlated with poor outcome in recipients best matched for HLA. Our results demonstrate that in patients with 0 or 1 HLA-A plus HLA-B plus HLA-DR mismatch, allograft survival was reduced among those with MICA antibodies (hazard ratio for allograft loss, 4.97; P=0.002). These results suggest that MICA antibodies exert an effect independent of HLA.
Baid-Agrawal and Frei ask if MICA antibodies can induce humoral or cellular rejection. Dragun et al. address a similar point. While it is, of course, possible that a cellular response may exist together with antibodies to MICA, as shown in mice immunized with recombinant MICA,1 we were unable to determine this in patients in our study. Our ongoing work will address the pathology associated with allograft failure in patients with antibodies against MICA and might prove informative about mechanisms of graft loss. In regard to other covariates, multivariate analysis found no significant effects on graft outcome for the covariates analyzed.
The paper by Scornik et al.,2 cited by Dragun et al., is of interest. Only one patient was found to have antibodies against MICA. It is not known whether the antibodies were reactive against MICA of the donor, or whether it was a false positive result, as is common with the commercial kits that were used by the authors. The statement that MICA antibodies did not correlate with rejection or C4d deposition appears to be based on this single observation.
2 ReferencesPeter Stastny, M.D.
Yizhou Zou, M.D.
University of Texas Southwestern Medical Center, Dallas, TX 75390-8886
peter.stastny@utsouthwestern. edu Gerhard Opelz, M.D.
University of Heidelberg, D-69117 Heidelberg, Germany1
Zhang Y ,Stastny P . MICA antigens stimulate T cell proliferation and cell-mediated cytotoxicity. Hum Immunol 2006;67:215-222
CrossRef | Web of Science | Medline2
Scornik JC ,Guerra G ,Schold JD ,Srinivas TR ,Dragun D ,Meier-Kriesche HU . Value of posttransplant antibody tests in the evaluation of patients with renal graft dysfunction. Am J Transplant 2007;7:1808-1814
CrossRef | Web of Science | Medline
